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Recurrence Pattern Analysis After Re-Irradiation with Bevacizumab in Recurrent Malignant Glioma Patients

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Recurrence Pattern Analysis After Re-Irradiation with Bevacizumab in Recurrent Malignant Glioma Patients Niyazi et al. Radiation Oncology (2014) 9:299 DOI 10.1186/s13014-014-0299-y RESEARCH Open Access Recurrence pattern analysis after re-irradiation with bevacizumab in recurrent malignant glioma patients Maximilian Niyazi1*, Nathalie Lisa Jansen2, Maya Rottler1, Ute Ganswindt1 and Claus Belka1 Abstract Background: The aim of the present analysis was to evaluate the recurrence pattern in patients with recurrent malignant glioma after re-irradiation in combination with bevacizumab as there is limited data on how to optimally choose dose, fractionation and delineation margins. Methods: Thirty-one patients with recurrent malignant glioma treated with re-irradiation and bevacizumab after previous chemoradiotherapy (concurrent temozolomide 75 mg/m2/d according to the EORTC/NCIC trial) and [18 F]FET-PET and/or MRI confirmed recurrence were retrospectively analyzed. Bevacizumab was applied twice during fractionated re-irradiation (10 mg/kg, d1 + d15, median 36 Gy, conventionally fractionated). Recurrence patterns were assessed by means of [18 F]FET-PET and/or MRI. Results: Median follow-up was 34.0 months for all patients [95%-CI, 27.7-40.3] and median post-recurrence survival 10.8 months [95%-CI, 9.2-12.4]. Concerning the recurrence patterns, 61.3% of these were located in-field (19 patients), 22.6% were marginal (7 patients) and 16.1% ex-field (5 patients). No influence on the recurrence pattern was observed according to sex, WHO grade, maintenance chemotherapy or MGMT methylation status whereas planning target volume (PTV) size had a significant influence on the recurrence pattern (p = 0.032). PTV sizes > 75 ml were associated with a higher in-field recurrence rate and lower median post-recurrence progression-free survival (8.5 vs. 4.9 months, p = 0.016). Conclusions: After the administration of re-irradiation with bevacizumab the recurrence pattern seems to be mainly centrally located. The PTV size was the main predictor for a marginal/ex-field recurrence. Keywords: Recurrence pattern, Re-irradiation, Bevacizumab, Glioblastoma Introduction drugs either alone or in combination with cytotoxic agents In patients with high-grade glioma (HGG) a high rate of are currently undergoing clinical testing. local failures has been observed after multimodal therapy Various groups have investigated the use of bevacizumab – [1]. The addition of temozolomide (TMZ) increased local a humanised monoclonal antibody against VEGF-A with control and survival whereas the 2-year survival rate an already established role in metastatic colon, breast, and remained 27.2% [2]. lung cancer [11] – for patients with recurrent HGG [12] In selected patients, a second course of radiotherapy and several trials have documented its efficacy [13-17] (RT) might be a reasonable treatment option despite the which may be due to the presence of pronounced hypoxia relative lack of prospective randomized data [3-6]. Con- as well as high levels of tumor driven angiogenesis in trarily, conventional cytotoxic approaches were found to HGG [18]. be not adequately effective [7-10] so molecularly targeted Since the efficacy of radiation-based re-treatment is lim- ited, it is reasonable to test how far the addition of a puta- tive radiation response modulator would impact on the * Correspondence: [email protected] 1Department of Radiation Oncology, University Hospital of Munich, efficacy of re-treatment. In this regard, one group tested Marchioninistr. 15, 81377 Munich, Germany the sequential use of radiosurgery and bevacizumab with Full list of author information is available at the end of the article © 2014 Niyazi et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Niyazi et al. Radiation Oncology (2014) 9:299 Page 2 of 6 favorable outcome [19]. Alternatively, Gutin and co-workers [18 F]FET-PET data acquisition and analysis determined the safety and efficacy of radiotherapy (RT) Dynamic PET scans were acquired on a Siemens ECAT and concomitant bevacizumab – for the GBM cohort, EXACT HR+ scanner (Siemens/CTI, Knoxville, TN, USA) progression-free survival at six months (PFS-6) was after intravenous injection of approximately 180 MBq 65% [20]. In a previous retrospective study on 30 recur- [18 F]FET according to a standardized protocol [26]. Data rent malignant glioma patients undergoing re-irradiation, were reconstructed by filtered back projection using a 20 treated with bevacizumab and 10 without bevacizumab Hann filter, corrected for scatter and attenuation and we showed that PFS-6 within the bevacizumab-treated afterwards transferred to a HERMES workstation (Hermes cohort was 72% and survival was significantly enhanced Medical Solutions, Sweden) for further data processing. [21]. With substantially longer follow-up and a higher pa- PET-based evaluation of recurrence was performed by tient number, the significant post-recurrence survival an experienced nuclear physician by assessment of the (PRS) benefit of bevacizumab could be confirmed within a maximal standardized uptake value within the tumour second study describing a beneficial treatment with a low corrected for the unspecific uptake in the background rate of side-effects [22]. Recent prospective phase III trials (SUVmax/BG > 1.6) in combination with a previously in- (AVAglio & RTOG 0825) were designed to prove the effi- troduced dynamic analysis of [18 F]FET kinetic uptake cacy of TMZ based radio-chemotherapy with bevacizumab behaviour [27]. Furthermore, the biological tumor vol- as first-line therapy but failed to show a survival benefit ume was assessed, which was defined by semi-automatic whereas significant and marginally significant progression- threshold-based calculation of a volume of interest. free survival benefits have been observed [23,24]. In our study we retrospectively analyzed the pattern of Radiotherapy re-recurrence in recurrent HGG patients undergoing re- By analogy with Combs et al. [28] patients received a total irradiation with bevacizumab as there is limited data on dose of 36 Gy in 18 fractions (2 Gy single doses) employing how to choose proper safety margins during radiotherapy 3D conformal radiotherapy or intensity-modulated radio- planning and furthermore, in how far the chosen fraction- therapy (IMRT) if adjacent critical structures were present. ation schedule yielded adequate local control rates. Planning target volume (PTV) was defined as gross tumor volume (GTV) plus 10 mm margin at maximum. GTV in- cluded the contrast enhancing lesion in T1w + Gd MRI. Material and Methods To ensure reproducibility patients were immobilized with Patient selection a thermoplastic mask system. Treatment planning was per- Only patients with histologically and/or [18 F]FET-PET/ formed using the Oncentra® treatment planning system MRI proven recurrence of high-grade gliomas (WHO (OTP MasterPlan®, Elekta, Crawley, UK). grades III + IV) and macroscopic tumor (maximum diameter 6 cm, multifocality per se was not a contraindi- Analysis of recurrence pattern cation) underwent re-irradiation, the interval between Recurrences were defined as “in-field” if more than 80% first radiotherapy and re-irradiation had to be 6 months of the tumour recurrence resided within the prescription at minimum. Another precondition was the absence of 95% isodose surface, and “marginal” if 20% to 80% of the meaningful alternative treatment options, e. g. complete lesion was inside the 95% isodose surface. In all other resection by re-surgery, interstitial brachytherapy or sys- cases, recurrences were defined as outside the radiation temic chemotherapy. field (“ex-field”) according to the study of Lee et al. [29]; in case of a multifocal recurrence, the part lying most Treatment schedule and follow-up distant to the initial tumour site was taken as reference. Before treatment, a gadolinium-enhanced brain MRI with gradient echo sequence and perfusion and/or a [18 F]FET- Statistics PET. Patients treated with bevacizumab received 10 mg/ Tumour progression was defined according RANO cri- kg at days 1 and 15 during re-irradiation. If TMZ was ap- teria [30] or by the appearance of new vital/progressive plied concomitantly in patients who had no previous pro- tumour lesions by means of dynamic [18 F]FET-PET. Post- gression after TMZ pre-treatment a dosage of 75 mg/m2 recurrence progression-free (PR-PFS) and post-recurrence daily was chosen. survival (PRS), measured from the beginning of re- Treatment outcome was evaluated on a regular basis irradiation to progression or death, respectively, or date of (every three months) by brain MRI as described by [25] last follow-up, were analyzed using the Kaplan-Meier and/or [18 F]FET-PET. method; 95% CIs were calculated using the associated esti- Adjuvant chemotherapy was prescribed on an individ- mated standard errors. The log-rank test was used to test ual basis as no standard has been defined yet but was the significance of the following prognostic variables: not defined as mandatory. MGMT promoter methylation status, age, surgery and Niyazi et al. Radiation Oncology (2014) 9:299 Page 3 of 6 pattern of disease recurrence. In view of their small number, Table 1 Patient characteristics, N = 31 patients with recurrence at RT margin were grouped with Characteristic Patients patients having an ex-field recurrence in the analysis of time Sex to progression. A logistic regression analysis was performed • Male 21 (67.7%) to determine variables with significant influence on the re- • Female 10 (32.3%) currence pattern. Proportions were compared using Fisher’s – exact test. A p-value ≤ 0.05 was considered significant. Median Age [y] 51.0 (18 67) The scientific use of retrospective data has been expli- Median KPS 80 (40 – 100) citly allowed by Bavarian federal law. Additionally, all • KPS < 70 8 (25.8%) patients agreed that their scientific data could be used.
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